aficamten vs placebo in adults with symptomatic obstructive hypertrophic cardiomyopathy (sequoia-hcm)

Conditions: Obstructive Hypertrophic Cardiomyopathy (oHCM)

Summary: the purpose of this study is to evaluate the efficacy and safety of aficamten (ck-3773274) versus placebo in adults with symptomatic hypertrophic cardiomyopathy (hcm) and left ventricular outflow tract obstruction.

cy 6031 was a phase 3, randomized, placebo-controlled, double-blind, multi-center trial in participants with symptomatic ohcm. eligible participants were randomized in a 1:1 ratio to receive aficamten or placebo. randomization was stratified by use of beta-blockers (yes or no) and cardiopulmonary exercise testing (cpet) exercise modality (treadmill or bicycle). enrollment limits were applied as follows: participants taking beta-blockers were capped at approximately 70% of total enrollment; participants taking disopyramide were capped at approximately 10% of total enrollment; participants with persistent atrial fibrillation (af) at screening were capped at approximately 15% of total enrollment; and participants using the bicycle cpet exercise modality were capped at approximately 50% of total enrollment. investigational product (ip) was administered orally once daily (qd) with or without food for 24 weeks. during the initial 6 weeks of the treatment period, ip doses were individually titrated at weeks 2, 4, and 6 based on echocardiography-guided criteria. dose escalation at weeks 2, 4, and 6 occurred only if a participant had a valsalva lvot-g ≥ 30 mmhg and a biplane left ventricular ejection fraction (lvef) ≥ 55%. echocardiograms were performed at each subsequent visit during the trial, and the ip dose was down-titrated if the lvef was \< 50%. the primary endpoint of peak oxygen uptake (pvo2) was measured by cpet at screening and at the end of treatment (week 24). a participant's background hcm therapy was individually optimized according to local practice prior to enrollment in the study.

Eligibility criteria:
key inclusion criteria: * males and females between 18 and 85 years of age, inclusive, at screening. * body mass index \<35 kg/m2. * diagnosed with hcm per the following criteria: * has lv hypertrophy and non-dilated lv chamber in the absence of other cardiac disease and * has an end-diastolic lv wall thickness as measured by the echocardiography core laboratory of: * ≥15 mm in one or more myocardial segments or * ≥13 mm in one or more wall segments and a known-disease-causing gene mutation or positive family history of hcm * has resting lvot-g ≥30 mmhg and post-valsalva lvot g ≥50 mmhg during screening as determined by the echocardiography core laboratory. * lvef ≥60% at screening as determined by the echocardiography core laboratory. * nyha functional class ii or iii at screening. * hemoglobin ≥10g/dl at screening. * respiratory exchange ratio (rer) ≥1.05 and pvo2 ≤90% predicted on the screening cpet per the core laboratory. * patients on beta-blockers, verapamil, diltiazem, or disopyramide should have been on stable doses for \>6 weeks prior to randomization and anticipate remaining on the same medication regimen during the trial. patients treated with disopyramide must also be concomitantly treated with a beta blocker and/or calcium channel blocker. key exclusion criteria: * known or suspected infiltrative, genetic or storage disorder causing cardiac hypertrophy that mimics ohcm (eg, noonan syndrome, fabry disease, amyloidosis). * significant valvular heart disease (per investigator judgment). * moderate-severe valvular aortic stenosis. * moderate-severe mitral regurgitation not due to systolic anterior motion of the mitral valve. * history of lv systolic dysfunction (lvef \<45%) or stress cardiomyopathy at any time during their clinical course. * inability to exercise on a treadmill or bicycle (eg, orthopedic limitations). * has been treated with septal reduction therapy (surgical myectomy or percutaneous alcohol septal ablation) or has plans for either treatment during the trial period. * documented paroxysmal atrial fibrillation during the screening period. * paroxysmal or permanent atrial fibrillation is only excluded if: * rhythm restoring treatment (eg, direct-current cardioversion, atrial fibrillation ablation procedure, or antiarrhythmic therapy) has been required ≤6 months prior to screening. * rate control and anticoagulation have not been achieved for at least 6 months prior to screening. * history of syncope or sustained ventricular tachyarrhythmia with exercise within 6 months prior to screening. * has received prior treatment with ck-3773274 or mavacamten.

Keywords: obstructive hypertrophic cardiomyopathy ohcm ck-3773274 ck-274 aficamten sequoia-hcm cy 6031 sequoia